Inhaled pharmaceutical aerosols are often deposited in the lung at very low deposition efficiencies. Perhaps more significant than the quantity of drug deposited is the large inter- and intra-subject variability that is often observed with these medicinal aerosols and the associated dose delivered to the lung. In order to make many next-generation inhaled medications a viable drug delivery alternative, increased lung delivery and decreased inter- and intra-subject variability are of critical importance. The objective of this study is to develop an approach for improved lung delivery and retention of nanoparticle and submicrometer aerosols using enhanced condensation growth. This concept consists of combining (1) a controlled inhalable water vapor humidity source with (2) a submicrometer aerosol generation and delivery device. The humidity source is used to create a controlled supersaturated relative humidity environment within general regions of the lung. This conditioning of the respiratory tract may be accomplished through an inhalation of supersaturated water vapor with pre-specified temperature and relative humidity (RH) conditions. The aerosol, in particle or droplet form, will be delivered either concurrently or following the controlled inhalation of the humidity source. The aerosol should have a size that can effectively penetrate the mouth-throat and upper tracheobronchial regions, e.g., approximately 1 [unreadable]m and below. Upon transport into the lung, the aerosol will increase in size due to enhanced condensation growth (water accumulation) in the controlled supersaturated environment, thereby increasing retention. To achieve this objective, the following specific aims are proposed: Specific Aim 1: Develop an in vitro system to evaluate the controlled enhanced condensation growth concept in the upper respiratory tract and assess the effects of RH under steady flow conditions. Specific Aim 2: Develop and validate a computational fluid dynamics (CFD) model of hygroscopic droplet growth in the upper tracheobronchial region and apply the model to evaluate aqueous wall boundary conditions and transport into distal bronchi. Specific Aim 3: Employ the developed in vitro and CFD models to test the effects of (1) transient flow, (2) aerosol concentration density, and (3) aerosol hygroscopic properties and physical form on the hygroscopic growth of 100 - 1000 nm aerosols. By delivering submicrometer aerosols past the mouth-throat and then increasing aerosol size through enhanced condensation growth, significant reductions in upper airway deposition and increased lung retention are expected. As a result, reduced variability in dose can be achieved, which is necessary for the effective use of many next-generation pharmaceutical aerosols. Public Health Relevance: A number of inhalable medications are in development for the treatment of respiratory diseases (such as lung cancer, respiratory infections, and cystic fibrosis) and systemic conditions (such as diabetes, chronic pain, and growth deficiency). However, the delivery of these next- generation inhaled pharmaceuticals to the lungs is often inefficient, which can significantly reduce drug effectiveness and increases unwanted side effects. The overall goal of this project is to develop a novel technology for the efficient delivery of inhaled medicines that minimizes deposition in the mouth and throat and maximizes deposition in the lungs.